U.S. patent application number 12/173447 was filed with the patent office on 2009-01-29 for amide addition reaction.
This patent application is currently assigned to Givaudan, SA.. Invention is credited to David C. Bom, David Max Dastrup, Stefan Michael Furrer, Ioana Maria Ungureanu.
Application Number | 20090030042 12/173447 |
Document ID | / |
Family ID | 39745177 |
Filed Date | 2009-01-29 |
United States Patent
Application |
20090030042 |
Kind Code |
A1 |
Furrer; Stefan Michael ; et
al. |
January 29, 2009 |
Amide Addition Reaction
Abstract
A method of making a compound of formula II ##STR00001##
comprising the reaction of a compound of formula RCONH.sub.2 with a
compound of formula III ##STR00002## R being a moiety having
between 1 and 15 carbon atoms and optionally from 1 to 5
heteroatoms independently selected from oxygen, nitrogen and
sulfur, and X and Y being independently selected front the group
consisting of H, methyl, ethyl, OMe, OEt, and mixtures thereof; the
reaction being performed in a solvent in the presence of a base.
The method is useful for the inexpensive manufacture of certain
commercially-valuable compounds, including some that have desirable
cooling properties.
Inventors: |
Furrer; Stefan Michael;
(Cincinnati, OH) ; Bom; David C.; (Cincinnati,
OH) ; Dastrup; David Max; (Liberty Twp., OH) ;
Ungureanu; Ioana Maria; (Cincinnati, OH) |
Correspondence
Address: |
CURATOLO SIDOTI CO., LPA
24500 CENTER RIDGE ROAD, SUITE 280
CLEVELAND
OH
44145
US
|
Assignee: |
Givaudan, SA.
Vernier
CH
|
Family ID: |
39745177 |
Appl. No.: |
12/173447 |
Filed: |
July 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60961656 |
Jul 23, 2007 |
|
|
|
Current U.S.
Class: |
514/332 ;
514/357; 546/265; 546/336 |
Current CPC
Class: |
C07D 213/127
20130101 |
Class at
Publication: |
514/332 ;
546/265; 514/357; 546/336 |
International
Class: |
A61K 31/444 20060101
A61K031/444; C07D 401/02 20060101 C07D401/02; A61K 31/44 20060101
A61K031/44; C07D 213/02 20060101 C07D213/02 |
Claims
1. A method of making a compound of formula II ##STR00008##
comprising reacting a compound of the formula RCONH.sub.2 with a
compound of formula III ##STR00009## R being a moiety having
between 1 and 15 carbon atoms and optionally from 1 to 5
heteroatoms independently selected from oxygen, nitrogen and
sulfur, and X and Y being independently selected from the group
consisting of H, methyl, ethyl, OMe, OEt, and mixtures thereof; the
reaction being performed in a solvent in the presence of a
base.
2. The method according to claim 1, in which R is a moiety selected
from the group consisting of arylalkenyl, heteroarylalkenyl,
arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl, and mixtures
thereof.
3. The method according to claim 2, in which R is selected from the
group consisting of 2,4-dimethylpent-3-yl, 2,3,4-dimethylpent-3-yl,
adamantyl, 2-isopropyl-5-methyl-cyclohexyl-1-yl, and mixtures
thereof.
4. The method according to claim 3, in which R is
2-isopropyl-5-methyl-cyclohexyl-1-yl in the (1R,2S,5R) form.
5. The method according to claim 1, in which the base is selected
from the group consisting of sodium hydroxide, potassium hydroxide,
potassium tert-butoxide, and mixtures thereof.
6. The method according to claim 1, in which the base is selected
from the group of sodium- and potassium-containing bases and the
solvent comprises at least one chelating agent.
7. The method according to claim 6, in which the chelating agent is
selected from the group consisting of solvents having chelating
properties and separately-added chelating agents.
8. The method according to claim 7, in which the chelating agent is
a crown ether.
9. The method according to claim 1, in which the reaction is
performed under conditions selected from at least one of elevated
temperature and elevated pressure.
10. The method according to claim 9, in which the elevated
temperature is at least about 50.degree. C.
11. The method according to claim 10, in which the elevated
temperature lies within the range of about 100.degree. to about
200.degree. C.
12. The method according to claim 1, in which R is a moiety of
formula IV ##STR00010## in which R.sup.1, R.sup.2 and R.sup.3
together comprise at least 6 carbons, and in which (a) (i) R.sub.1
is selected from the group consisting of H, Me, Et, isopropyl,
C.sub.4-C.sub.5 branched alkyl, and mixtures thereof; and (ii)
R.sub.2 and R.sub.3 are independently selected from the group
consisting of Me, Et, isopropyl, C.sub.4-branched alkyl, and
mixtures thereof; or (b) any two or all of R.sub.1, R.sub.2 and
R.sub.3 together form a monocyclic, bicyclic or tricyclic radical
having up to 10 carbons.
13. The method according to claim 12, in which the monocyclic,
bicyclic or tricyclic radical is selected from 3-para-menthyl,
bornyl, adamantyl, and mixtures thereof.
14. The method according to claim 12, in which R is
2-isopropyl-5-methyl-cyclohexyl-1-yl, optionally in the (1R, 2S,
5R) form.
15. A compound of formula II ##STR00011## prepared by the method
according to claim 1.
16. A compound of formula II according to claim 15, wherein R is a
moiety selected from the group consisting of arylalkenyl,
heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl,
alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and mixtures
thereof.
17. A compound of formula II according to claim 16, wherein R is
selected from the group consisting of 2,4-dimethylpent-3-yl,
2,3,4-dimethylpent-3-yl, adamantyl,
2-isopropyl-5-methyl-cyclohexyl-1-yl, and mixtures thereof.
18. A compound of formula II according to claim 17, wherein R is
2-isopropyl-5-methyl-cyclophexyl-1-yl in the (1R, 2S, 5R) form.
19. A compound of formula II according to claim 15, wherein R is a
moiety of formula IV ##STR00012## in which R.sup.1, R.sup.2 and
R.sup.3 together comprise at least 6 carbons, and in which (a) (i)
R.sub.1 is selected from the group consisting of H, Me, Et,
isopropyl, C.sub.4-C.sub.5 branched alkyl, and mixtures thereof;
and (ii) R.sub.2 and R.sub.3 are independently selected from the
group consisting of Me, Et, isopropyl, C.sub.4-branched alkyl, and
mixtures thereof; or (b) any two or all of R.sub.1, R.sub.2 and
R.sub.3 together form a monocyclic, bicyclic or tricyclic radical
having up to 10 carbons.
20. A compound of formula II according to claim 19, wherein the
monocyclic, bicyclic or tricyclic radical is selected from
3-para-menthyl, bornyl, adamantyl, and mixtures thereof.
Description
[0001] This application claims the benefits of the filing date of
U.S. Provisional Application for Patent Ser. No. 60/961,656, filed
Jul. 23, 2007, incorporated herein by reference.
[0002] This disclosure relates to the addition of carboxamides to
vinyl pyridines.
[0003] N-substituted p-menthane carboxamides are well known in the
art as compounds that impart a cooling sensation to the skin or the
mucous membranes of the body. Typical examples of such compounds
are described in, for example, British Patent GB 1,421,744.
[0004] In International Application PCT/CH2006/000427 there are
disclosed compounds of the general formula I
##STR00003##
[0005] in which X, Y, Z, R.sup.1, R.sup.2, R.sup.3 and m are as
defined in that document. In particular examples, at least two of
R.sup.1, R.sup.2, R.sup.3 together form a cyclic radical.
[0006] These compounds have usually been prepared by the reaction
of a menthane carboxylic acid chloride with a suitable monoamine.
One example of this is the following reaction:
##STR00004##
[0007] Although efficient, this reaction involves the use of
expensive materials.
[0008] It has now been found that it is possible to prepare such
compounds by a simple, inexpensive process. There is therefore
provided a method of making a compound of formula II
##STR00005##
[0009] comprising the reaction of a compound of the formula
RCONH.sub.2 with a compound of formula III
##STR00006##
[0010] R being a moiety having between 1 and 15 carbon atoms and
optionally from 1 to 5 heteroatoms independently selected from
oxygen, nitrogen and sulfur, and X and Y being independently
selected from the group consisting of H, methyl (Me), ethyl (Et),
OMe, OEt and mixtures thereof:
[0011] the reaction being performed in a solvent in the presence of
a base.
[0012] There is also provided a compound of the formula II as
hereinabove defined, prepared by a process as hereinabove
defined.
[0013] The compounds of formula III are vinyl pyridines, optionally
substituted. Either the 2- or the 4-vinyl pyridine or derivatives
thereof may be used.
[0014] The solvent may be any suitable solvent. It may be capable
of dissolving all the reactants and the reaction product. Useful
solvents include oxygen- and nitrogen-containing non-reactive
solvents and aromatic hydrocarbons. Non-limiting examples of
solvents include xylene, toluene, dimethyl formamide and
tetrahydrofuran (THF).
[0015] The quantity of solvent present is any suitable
quantity.
[0016] The base for use in the process may be any suitable base.
Typical examples of suitable bases include sodium methoxide,
potassium tert-butoxidc, lithium diisopropyl amine, sodium hydride,
sodium hydroxide and potassium hydroxide. A acceptable
concentration range is from about 0.01 to about 0.5
equivalents.
[0017] Particular examples of bases include sodium hydroxide,
potassium hydroxide and potassium tert-butoxide. These may be used
at concentration ranges of from about 0.05 to about 0.25
equivalents.
[0018] In particular embodiments involving the use of sodium or
potassium bases, the mixture may comprise a chelating agent. This
permits higher yields and faster reaction limes. Examples of
suitable chelating agents include crown ethers, such as 18-crown-6,
particularly in combination with bases such as potassium, hydroxide
and potassium tert-butoxide.
[0019] Alternatively, the solvent itself may be selected such that
it has chelating properties. If such solvents are used, a separate
chelating agent may be used in a reduced quantity or even omitted
altogether. Solvents that are useful in this regard include
dimethyl formamide (DMF), N-methylpyrrolidone (NMP). Combinations
of all or any these solvents may be used in any desired
proportions.
[0020] In a particular embodiment, the reaction is heated or
performed under pressure, for example, in a bomb or in a sealed
microwave vessel. While it is generally not essential to do this,
the use of such measures can lead to higher yields and faster
reaction times. A particular temperature range for healing is al
least about 50.degree. C., more particularly from about 100.degree.
to about 200.degree. C. Naturally, the use of higher temperatures
will have an effect on the selection of solvent, but the skilled
person will be able to select suitable solvents for each case.
[0021] Particular embodiments of the compound are those in which R
is selected according to the description hereinafter provided.
[0022] In particular embodiments. R is selected from arylalkenyl,
heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl,
alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl moieties,
and mixtures thereof.
[0023] Particular examples of R include (but are not limited to)
2,4-dimethylpent-3-yl, 2,3,4-dimethylpent-3-yl, adamantyl and
2-isopropyl-5-methyl-cyclohexyl-1-yl (in particular embodiments,
the (1R, 2S, 5R) form).
[0024] In a certain embodiment, the process is particularly useful
for producing the compounds of International Application
PCT/CH2006/000427 hereinabove described. In such a case, R is a
moiety of formula IV
##STR00007##
[0025] in which R.sub.1, R.sub.2 and R.sub.3 together comprise at
least 6 carbons, and are selected such that [0026] (a) (i) R.sub.1
is selected from the group consisting of H, Me, Et, isopropyl and
C.sub.4-C.sub.5 branched alkyl; and [0027] (ii) R.sub.2 and R.sub.3
are independently selected from the group consisting of Me, Et,
isopropyl and C.sub.4-branched alkyl; or [0028] (b) any two or all
of R.sub.1, R.sub.2 and R.sub.3 together form a monocyclic,
bicyclic or tricyclic radical having up to 10 carbons.
[0029] Examples of cyclic radicals as described under (b) above
include 3-para-menthyl, bornyl and adamantyl.
[0030] A particular example of Formula IV is
2-isopropyl-5-methyl-cyclohexyl-1-yl (in a particular embodiment,
the (1R, 2S, 5R) variant).
[0031] The method is now described with reference to the following
non-limiting examples.
EXAMPLE 1
Preparation of
N-(2-pyridin-2-ylethyl)p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]
[0032] In a 15 mL round bottom flask, fitted with magnetic stirrer
and reflux condensor, 0.368 g of p-menthanecarboxamide, 4 mL of
toluene, 0.32 mL of 2-vinyl pyridine, 0.027 g of 18-crown-6 and
0.12 ml, of potassium tert-butoxide (20% in THF) were added. The
mixture was heated at 110.degree. C. for 3 hours, yielding 97%
conversion by GC.
EXAMPLE 2
Preparation of
N-(2-pyridin-2-ylethyl)p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]
[0033] In a 5 mL Biotage microwave vial, fitted with magnetic
stirrer, 0.1 g of p-menthanecarboxamide, 0.55 mL of toluene, 0.45
mL of NMP, 0.086 g of 2-vinyl pyridine and 3.1 mg of KOH were
added. The vial was sealed and heated in the Biotage microwave
instrument at 150.degree. C. for 10 min, yielding 90.9% conversion
by GC.
EXAMPLE 3
Preparation of
N-(2-pyridin-2-ylethyl)p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-yl)ethyl)cyclohexanecarboxamide]
[0034] In a 5 mL Biotage microwave vial, fitted with magnetic
stirrer, 0.1 g of p-menthanecarboxamide, 1.0 mL of THF, 0.086 g of
2-vinyl pyridine and 0.1 eq. of potassium tert-butoxide (KOtBu)
(20% in THF) were added. The vial was sealed and heated in the
Biotage microwave instrument at 160.degree. C. for 20 min, yielding
88% conversion by GC.
EXAMPLE 4
Preparation of
N-(2-pyridin-2-ylethyl)p-menthanecarboxamide[(1H,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]
[0035] In a 5 mL Biotage microwave vial, fitted with magnetic
stirrer, 0.1 g of p-menthanecarboxamide, 1.0 mL of NMP, 0.086 g of
2-vinyl pyridine and 0.1 eq. of KOtBu (20% in THF) were added. The
vial was sealed and heated in the Biotage microwave instrument at
150.degree. C. for 10 min, yielding 95.3% conversion by GC.
EXAMPLE 5
Preparation of
N-(2-pyridin-2-ylethyl)p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]
[0036] In a 5 mL Biotage microwave vial, fitted with magnetic
stirrer, 0.1 g of p-menthanecarboxamide, 1.0 mL of NMP, 0.086 g, of
2-vinyl pyridine and 2.2 mg of NaOH were added. The vial was sealed
and heated in the Biotage microwave instrument at 150.degree. C.
for 10 min, yielding 85.7% conversion by GC.
EXAMPLE 6
Preparation of
N-(2-pyridin-2-ylethyl)p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]
[0037] In a 5 mL Biotage microwave vial, fitted with magnetic
stirrer, 0.1 g of p-menthanecarboxamide, 0.05 mL of NMP, 0.95 mL of
toluene, 0.082 mL of 2-vinyl pyridine and 3.1 mg of KOH were added.
The vial was sealed and heated in the Biotage microwave instrument
at 150.degree. C. for 10 min, yielding 74.6% conversion by GC.
EXAMPLE 7
Preparation of
N-(2-pyridin-2-ylethyl)p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]
[0038] In a 100 mL round bottom flask, fitted with magnetic stirrer
and reflux stirrer, 5.0 g of p-menthanecarboxamide, 10 mL of NMP,
and 150 mg of KOH were added. The mixture was heated for 1 hour at
120.degree. C.
[0039] The mixture was cooled to room temperature and 60 mL of
water were added slowly under stirring, while crystals separated
from the mixture. The mixture was cooled to 0.degree. C., filtered
and the crystals were washed limes with ice cold water. The crude
product was re-crystallized from ethyl acetate and hexane, yielding
3.96 g of white crystals (50% yield).
[0040] MS: 288 ([M.sup.+*]), 273, 245, 149, 121, 95
[0041] .sup.1H NMR (300 MHz; DMSO) .delta.: 8.53 (d, 111), 7.62
(td, 1H), 7.16 (m, 2H), 6.43 (s, 1H), 3.67 (nontuplet, 2H), 3.00(t,
2H), 1.95 (td, 1H), 1.84-1.53 (m, 4H), 1.47 (broad t, 1H), 1.4-1.1
(m, 2H), 0.87 (d, 3H), 0.84 (d,3H), 0.66 (d, 3H)
[0042] .sup.13C NMR (75 MHz; DMSO) .delta.: 175.8, 159.7, 148.9,
136.7, 123.6, 121.55, 49.8, 44.3, 39.4, 38.35, 36.9, 34.6, 32.3,
28.55, 23.9, 22.3, 21.3, 15.95
EXAMPLE 8
Preparation of
N-(4-pyridin-2-ylethyl)p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-met-
hyl-N-(2-(pyridin-4-ethyl)cyclohexanecarboxamide]
[0043] In a 5 mL Biotage microwave vial, fitted with magnetic
stirrer, 0.1 g of p-menthanecarboxamide, 1 mL of NMP, 0.082 mL of
4-vinyl pyridine and 3.1 mg of KOH were added. The vial was sealed
and heated in the Biotage microwave instrument at 150.degree. C.
for 10 min, yielding 54% conversion by GC.
[0044] MS: 260 ([M.sup.+*]), 217, 149, 121, 95
EXAMPLE 9
Preparation of
2-isopropyl-2,3-dimethyl-N-(2-(pyridin-2-yl)ethyl)butanamide
[0045] In a 20 mL Biotage microwave vial, fitted with magnetic
stirrer, 1.0 g of 2-isopropyl-2,3-dimethylbutanamide, 10 mL of
toluene, 1.0 g of 2-vinyl pyridine, 0.027 g of 18-crown-6 and 0.18
g of potassium tert-butoxide (20% in THF) were added. The vial was
sealed and heated in the Biotage microwave instrument at
200.degree. C. for 30 min.
[0046] The mixture was acidified with 100 mL of HCl (1N in water)
and 2 times extracted with MTBE. The aqueous layer was treated with
150 mL of NaOH (1N in water) and extracted 2 times with MTBE. The
organic layer was dried over magnesium sulfate, concentrated and
purified by column chromatography. 1.17 g of white crystals were
obtained (70% yield).
[0047] Mp: 60-61.degree. C.
[0048] MS: 262 ([M+]), 220, 205, 149, 121, 106, 93
[0049] .sup.1H NMR (300 MHz; CDCl3) 8.53 (d, 1H), 7.63 (t, 1H),
7.16 (m, 2H), 6.69 (s, 1H), 3.67 (dd, 2H), 2.99 (t, 2H), 1.96 (m,
2H), 0.96 (s, 3H), 0.85 (d, 6H), 0.79 (d, 6H)
[0050] .sup.13C (75 MHz; CDCL3) 175.6, 160.0, 149.1, 136.6, 123.4,
121.5, 51.4. 38.4, 36.9, 32.6, 18.1, 17.4, 14.1
EXAMPLE 10
Preparation of 2-phenyl-N-(2-(pyridin-2-yl)ethyl)butanamide
[0051] In a 10 mL Biotage microwave vial, fitted with magnetic
stirrer, 2.5 g of 2-phenylbutyramide, 3 mL of NMP, 1.6 g of 2-vinyl
pyridine, 0.1 g of KOH were added. The vial was sealed and heated
in the Biotage microwave instrument at 150.degree. C. for 10
min.
[0052] The mixture poured on ice, the pH was adjusted with NaOH (1N
in water) to pH 12 and extracted with MTBE. The organic layer was
washed with brine, dried over magnesium sulfate, concentrated and
purified by column chromatography. 2.3 g of beige oil were obtained
(56% yield).
[0053] MS: 266 ([M+]), 253, 240, 149, 121, 106, 91, 78, 65
[0054] .sup.1H NMR (300 MHz; CDCl3) 8.40 (m, 1H), 7.50 (dt, 1H),
7.3-7.2 (m, 5H), 7.1 (dt, 1H), 7.0 (d, 1H), 6.35 (s, 1H), 3.60 (dd,
2H), 3.20 (t, 1H), 2.90 (t, 2H), 2.2-2.1 (m, 1H), 1.8-1.7 (m, 1H),
0.84 (t, 3H)
[0055] .sup.13C (75 MHz; CDCl3) 173.5, 159.6, 149.1, 140.0, 136.5,
128.6, 128.1, 127.0, 123.4, 121.4, 55.4, 38.8, 36.8, 26.1, 12.3
EXAMPLE 11
Preparation of
2-(2-methoxybenzylamino)-N-(2-(pyridin-2-yl)ethyl)acetamide
[0056] In a 10 mL Biotage microwave vial, fitted with magnetic
stirrer, 2.5 g of 2-(2-methoxybenzylamino)acetamide, 3 mL of NMP,
1.6 g of 2-vinyl pyridine, 0.1 g of KOH were added. The vial was
sealed and heated in the Biotage microwave instrument at
150.degree. C. for 10 min.
[0057] The mixture poured on ice, the pH was adjusted with NaOH (1N
in water) to pH 12 and extracted with MTBE. The organic layer was
washed with brine, dried over magnesium sulfate, concentrated and
purified by column chromatography. 1.05 g of beige oil were
obtained (27% yield).
[0058] MS: 299 ([M+]), 178, 164, 150, 136, 121, 106, 91, 78, 65,
51
[0059] .sup.1H NMR (300 MHz; CDCl3) 8.50 (m, 1H), 7.80 (s, 1H), 7.6
(dt, 1H), 7.3-7.1 (m, 4H), 7.0-6.8 (m, 2H), 3.82 (s, 3H), 3.75-3.65
(m, 2H), 3.65 (s, 2H), 3.23 (s, 2H), 3.05 (t, 2H), 1.95 (s, 1H)
[0060] .sup.13C (75 MHz; CDCL3) 171.8, 159.4, 157.6, 149.4, 136.4,
129.9, 128.6, 123.4, 121.5, 120.5, 110.3, 55.2, 51.8, 49.4, 38.3,
37.6
[0061] These examples are for the purpose of illustration only and
it is understood that variations and modifications can be made by
one skilled in the an without departing from the spirit and the
scope of the invention. It should be understood that the
embodiments described are not only in the alternative, but, can be
combined.
* * * * *